# Deterrents for prescription opioid abuse

> **NIH NIH R01** · UNIVERSITY OF MISSISSIPPI MED CTR · 2024 · $547,213

## Abstract

Project Summary
Mu opioid receptor (MOR) agonists are the most effective treatments for moderate to severe acute
pain, but their high abuse liability and risk for lethal overdose have exacted a significant toll on public
health in recent years. Our program of study has investigated the feasibility of combining MOR
agonists with kappa opioid receptor (KOR) agonists to deter abuse and enhance pain-decreasing
effects. Our findings from Project Period 1 of this program indicate that the atypical KOR agonist,
nalfurafine, decreases oxycodone’s abuse-related effects and enhances analgesia, but nalfurafine
also produced significant sedative effects on its own. Recently, new KOR agonists have been
developed that are reported to produce even fewer of the adverse behavioral effects that are typical
of the KOR-agonist class. These atypical KOR agonists have been described as “G-protein biased”
due to their greater potency to activate G-protein signaling relative to other pathways at the KOR. Our
preliminary data indicate that the biased KOR agonist, triazole 1.1, is more therapeutically selective
than nalfurafine. However, it is unknown if the positive characteristics observed with triazole 1.1 are
due to G-protein bias or other potential mechanisms peculiar to the structural class. The overall goal
of this renewal application is to systematically investigate combinations of oxycodone with new
atypical KOR agonists that are reported to be G-protein biased from different structural classes to
determine if reported signaling bias is associated with increased therapeutic selectivity (decreased
abuse potential; enhanced antinociception) and reduced KOR-mediated “side effects”. To accomplish
this goal, we will use complementary animal models (rhesus monkeys and rats) and rigorous
quantitative pharmacology to determine if the atypical KOR agonists can reduce oxycodone’s abuse-
related effects (Specific Aim 1), augment oxycodone’s pain-decreasing effects (Aim 2), and produce
fewer side effects when combined with oxycodone (Aim 3). We will relate the relative potencies of the
various KOR agonists to produce therapeutic and unwanted side effects to identify optimal leads for
future development of therapeutics that activate MORs and KORs (dual-acting molecules; drug
combinations). The studies proposed in this renewal will positively impact public health by laying the
groundwork for the development of non-addictive pain medications that will retain the high treatment
efficacy of current prescription opioids.

## Key facts

- **NIH application ID:** 10834892
- **Project number:** 5R01DA039167-09
- **Recipient organization:** UNIVERSITY OF MISSISSIPPI MED CTR
- **Principal Investigator:** Kevin B. Freeman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $547,213
- **Award type:** 5
- **Project period:** 2015-09-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10834892

## Citation

> US National Institutes of Health, RePORTER application 10834892, Deterrents for prescription opioid abuse (5R01DA039167-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10834892. Licensed CC0.

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